Project Summary The goal of this grant renewal is to develop theory and large-scale circuit modeling of the primate cortex with many interconnected areas, for distributed working memory and flexible decision processes as well as its dopamine modulation. This research program is designed to meet the challenge of understanding cognition beyond local circuits towards the complex global brain. The proposed work is now feasible thanks to recently available mesoscopic directed- and weighted data for inter-areal connections of macaque cortex. We have already published several papers on the development of a large-scale, multi-regional dynamical cortical circuit model of macaque monkey, including a population rate model endowed with a laminar cortical structure and a spiking network model. Our computational work will be undertaken in collaborations with five experimental labs working on macaque monkeys (Earl Miller (MIT), John Duncan (Oxford University, UK), Stefan Everling (Western University, Ontario, Canada), Henry Kennedy (ISERM, Lyon, France) and Karl Zilles (Jlich University, Germany)). Specific Aim 1 will be to build a large-scale cortical circuit model of macaque monkey for distributed working memory. Hypothesis: distributed self-sustained activity patterns underlying working memory depend on a combination of the mesoscopic inter-areal connection properties and gradients of circuit properties across a brain?s hierarchy. Specific Aim 2 will be to investigate high-dimensional dynamics of persistent activity underlying a high degree of temporal variations. Hypothesis: NMDA/AMPA receptor ratio is higher at top-down projections than bottom-up ones, and there is a macroscopic gradient of short-term plasticity. The two combined contribute to complex spatiotemporal mnemonic neural population activity that is better described by trajectories in a high-dimensional state space. Specific Aim 3 will be to expand the model to simulate decision- making and rule-based flexible sensorimotor behavior. Hypothesis: the same model endowed with different representations (spatial location, object features such as color and motion direction, rule encoding, respectively) in different cortical areas can be used to simulate rule-based flexible decision tasks as well as working memory tasks. Specific Aim 4 will be to study of neuromodulation and NMDA deficits of this large-scale primate cortical model. Hypothesis: dopamine modulation displays a macroscopic gradient along the cortical hierarchy, and impairment of NMDA receptors preferentially affects top-down rather than bottom-up signaling in the global brain. Taken together, the proposed research will shed fundamental insights into complex dynamics and cognitive functions in the global brain. It will also yield a pioneering and powerful computational platform for basic research on large-scale brain systems of the primates, as well as cross-level circuit mechanistic studies of psychiatric disorders like Schizophrenia.